Conserved neuronal-like and secretory programs define the spatial architecture of gastroenteropancreatic neuroendocrine tumors.

Authors

Julie Karam, Samantha E Hoffman, Amanda Garza, Dan Gui, Hannah I Hoffman, Breanna M Titchen, Yutaro Tanaka, Erica Pimenta, Theodora Pappa, Laura Valderrabano, Kevin Bi, Riaz Gillani, Lauren Brais, Erin Shannon, Jason L Hornick, Jihye Park, Jennifer Chan, Eliezer M Van Allen

Published in

The Journal of clinical investigation. Sep 01, 2026. Epub Sep 01, 2026.

Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood. Here, we integrated single-nucleus multiomic (snRNA-seq and snATAC-seq) and spatial transcriptomic profiling across 38 well-differentiated pancreatic (PanNET) and small-intestinal (siNET) tumors to define conserved malignant programs, their regulatory circuits, and spatial niches. We observed two conserved malignant cell programs spanning a continuous transcriptional spectrum: a neuronal-like program, and a secretory neuroendocrine program. Matched chromatin accessibility profiles uncovered distinct, tissue-specific regulatory networks, including MAX::MYC and MITF transcription factor binding motifs in siNETs versus ISL1 and TFAP4 in PanNETs, indicating organ-specific epigenetic control. Spatial transcriptomic analyses revealed that neuronal-like-high regions localized to densely cellular tumor areas with relative depletion of stromal infiltration, whereas secretory neuroendocrine-high regions occupied fibrovascular and stromal niches enriched for endothelial, fibroblast, and myeloid populations, and associated with TGFB1-ITGB1, VEGFA-FLT1, and LAMA2-ITGA1 signaling. Across both tumor types, the cNMF2 program was enriched in metastatic lesions and was enriched for pro-fibrotic and pro-angiogenic gene signatures. Thus, GEP-NETs are organized along a conserved neuronal-to-secretory axis defined by distinct epigenetic programs and spatially coupled to specific microenvironmental niches. This framework unifies NET heterogeneity across organ sites and identifies pathway-specific, microenvironment-linked vulnerabilities for therapeutic targeting.

PMID:
42678737
Bibliographic data and abstract were imported from PubMed on 02 Sep 2026.

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